Sexual dimorphism in gene expression is widespread across chromosomes, and is partially conserved across species from mice to humans, the first study to investigate such differences both across species and across tissues has found.

But though there was much sex bias, there was little sex binary. "In males and females, many sliders are being moved a little bit," David Page told BioWorld.

"Tremendous power and insight have been provided by the binary of testes and ovary, X and Y, egg and sperm – and all of these binaries are real," he added.

But overall, his team's work implies that "even biological sex in the strictest, narrowest sense is not about the XX and XY, and not just about sex hormones – the whole genome is in the game... I think this begins to open the door to much more nuanced ideas that can incorporate and ultimately provide some ways of thinking about, for example, gender fluidity."

Page is professor of biology at the Massachusetts Institute of Technology, the director of the Whitehead Institute, and the corresponding author of the paper reporting those results in the July 20, 2019, issue of Science.

In that paper, the team looked at 12 tissues from brain to spleen in five different species – mice, rats, dogs, macaques, and humans, and found hundreds of genes with conserved sex-biased expression in each tissue.

The differences in gene expression Page and his team reported in their work were typically akin to sex differences in height. Though there is a robust and biologically determined difference in average height between males and females, it is impossible to accurately gauge someone's sex from their height alone.

Page's team also looked closely at genes that were tilted male or female consistently across species in their study, and showed that they could explain part of the male-female difference in average height.

Height, Page said, is "the most intensely studied trait in quantitative genetics" and a testing ground for the development of analytical methods.

But though studies have identified hundreds of minor contributors to height, "have never provided insight into why males are taller on average than females."

One question that Page and his team have not yet addressed, though they plan to, is how autosomal chromosomes "know" they are male and female.

"We have tended to view the differences between males and females being neatly packaged on the X and Y chromosomes," Page said. "What we're pointing to are differences in, let's say, chromosome 5."

The question then becomes "How does chromosome 5 know that it's in a male or female and why does it behave a little differently?"

"There's a whole set of ideas that now need to be developed," Page said.

Differences in gene expression on the sex chromosomes that then modulate the expression of genes on autosomal chromosomes are one possibility, and gene modulation by sex hormones is another.

In their current studies, the team observed some cases of genes with sex-biased expression "coming under control of a transcription factor that is itself sex-biased" in a domino effect. "Once you get a few, others can be recruited."

Practice and philosophy

The work has practical implications for the biopharmaceutical industry. "A good bit of gene expression sex bias is conserved, but the great majority of it is not," Page said. If we are looking to model in nonhuman models – as we do – then we need to understand [which] sex biases are also conserved across species."

In pharmaceutical development, drugs can also "fall out of pipelines for any number of reasons, including untoward consequences in one sex or the other," and better understanding of those risks could point to strategies to mitigate them.

But in its demonstration that many aspects of sex are a continuum at the molecular level, Page said, "the importance of the work derives from the way it may point to the future."

Scientifically speaking, sex and gender are everywhere and nowhere.

"We have for decades, if not centuries, been operating with a fundamentally unisex model of human biology," he said. "It's convenient to shunt sex to the side."

It does make for poor science, though.

"There are profound differences in the way disease ... plays out in males and females," he pointed out. Autism spectrum disorders affect males and females at a ratio of four to one, and "most autoimmune diseases are far more common in females than in males. And we simply do not know why that is the case ... If we knew of any other factor that increased your risk of disease by a factor of four, the whole research world would focus on it."

It is only recently that women have routinely been included in NIH-funded clinical trials, and attempts to ensure the inclusion of female animals in preclinical studies are more nascent still.

That state of affairs is ironic given that "sex and gender is personal for everybody – there is nobody for whom this is an arm's length question," Page said. "There is no one whose existence is untouched or uninterested or unaffected."

Page himself said that throughout his career, which has included sequencing the Y chromosome and mapping Y-linked genes, larger issues around sex and gender "were always in my peripheral vision."

Partly because those larger issues are personal for everyone, partly because they can be a third rail, and partly for other reasons, "the scientific discourse there gets quite muddy," he said. Currently, there is "not even much curious inquiry."

The work now published in Science, he said, was undertaken in part out of "the desire to take a first step towards understanding male-female differences ... I'm excited about the possibility of a way forward."

And, he predicted, "the future will, unless we keep it from happening, be a much more synthesized, integrated view of binary and nonbinary."

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